Author Affiliations: California Poison Control System, San Diego Division, University of California San Francisco School of Pharmacy, San Diego (Dr Cantrell); Department of Emergency Medicine, University of California, Irvine Medical Center, Orange (Dr Suchard); and Department of Laboratory Medicine, San Francisco General Hospital/University of California San Francisco, San Francisco (Drs Wu and Gerona).

Debate exists regarding the relative potency of medications beyond their labeled expiration dates. Expired medications have not necessarily lost potency, since the expiration date is only an assurance that the labeled potency will last at least until that time.1 Clinical situations may arise in which expired drugs might be considered owing to lack of viable alternatives2 or financial concerns.3 Ongoing studies show that many medications retain their potency years after their initially labeled expiration dates.4 We sought to characterize the potency of some prescription medications that had expired decades ago.

METHODS

Eight long-expired medications with 15 different active ingredients were discovered in a retail pharmacy in their original, unopened containers. All had expired 28 to 40 years prior to analysis. Three tablets or capsules of each medication were analyzed, with each sample tested 3 times for each labeled active ingredient. No analytical standard for homatropine could be found, so that ingredient was not tested.

Tablets or capsule contents were dissolved and sonicated in methanol, reconstituted in analysis buffer (10% methanol) and analyzed with Liquid Chromatograph (Agilent Technologies) Time-of-Flight Mass Spectrometer (Agilent) using electrospray ionization in negative and positive polarities. Chromatography was run with gradient elution using Eclipse Plus C18 column (Agilent). Data analysis was performed using Mass Hunter Qualitative and Quantitative Analysis (Agilent). Quantification was performed by isotope dilution method with a 6-point calibration curve.

RESULTS

Twelve of the 14 drug compounds tested (86%) were present in concentrations at least 90% of the labeled amounts, the generally recognized minimum acceptable potency. Three of these compounds were present at greater than 110% of the labeled content. Two compounds (aspirin and amphetamine) were present in amounts of less than 90% of labeled content. One compound (phenacetin) was present at greater than 90% of labeled amounts from 1 medication tested, but less than 90% in another medication that contained that drug (Table).

COMMENT

The US Food and Drug Administration (FDA) permits “reasonable variation,” such that most medications marketed in the United States contain 90% to 110% of the amount of the active ingredient claimed on the label.5 Drug expiration dates typically range from 12 to 60 months after their production.4 However, FDA regulations do not require determination of how long medications remain potent after that, allowing manufacturers to arbitrarily establish expiration dates without determining actual long-term drug stability.

The Shelf-Life Extension Program (SLEP) checks long-term stability of federal drug stockpiles. Eighty-eight percent of 122 different drugs stored under ideal environmental conditions had their expiration dates extended more than 1 year, with an average extension of 66 months and a maximum extension of 278 months.4 In our data set, 12 of 14 medications retained full potency for at least 336 months, and 8 of these for at least 480 months. Given our inability to confirm ideal storage conditions for our samples, our results support the effectiveness of broadly extending expiration dates for many drugs, the efficacy of which has been demonstrated by SLEP in a more controlled fashion.

The 3 drugs found with less than 90% of their labeled potency were amphetamine and aspirin in both samples tested and phenacetin in 1 of 2 samples tested. Aspirin is known to degrade in vitro,6 but there are no such published data regarding amphetamine. For phenacetin, the difference in recovery between the 2 samples could be due to differences in packaging or storage of the containers. Aside from aspirin, all drugs in Fiorinal (butalbital, aspirin, caffeine, and codeine phosphate) had almost 100% of labeled concentrations, while those of Codempiral No. 3 (phenacetin with codeine phosphate) were all less than 95%. Since the codeine measured in Codempiral No. 3 was also lower than that of Fiorinal (90% vs 99%), this suggests that Codempiral's packaging was less intact, allowing moisture to penetrate, which can promote hydrolysis. Because phenacetin has an amide functional group, it is more prone to this type of degradation than codeine.

Three drugs were unexpectedly found in our samples at potencies greater than 110% of the labeled amounts. Some samples may have been produced prior to 1963, when FDA-mandated quality control measures were instituted (Paula R. Katz, Regulatory Counsel, FDA, Center for Drug Evaluation and Research, Division of Manufacturing and Product Quality, Guidance and Policy; e-mail communication, May 23, 2011); however, exact dating of all our samples was not possible. Alternately, these drugs could have come from lots untested by the manufacturer, or the accuracy between analytical methods used in this study compared with those used decades ago could be questioned.

The most important implication of our study involves the potential cost savings resulting from lengthier product expiration dating. Each dollar spent on SLEP to demonstrate longer than labeled drug stability results in $13 to $94 saved on reacquisition costs.4 Given that Americans currently spend more than $300 billion annually on prescription medications,7 extending drug expiration dates could yield enormous health care expenditure savings.

In conclusion, this study provides additional evidence that many prescription pharmaceuticals retain their full potency for decades beyond their manufacturer-ascribed expiration dates. Given the potential cost-savings, we suggest the current practices of drug expiration dating be reconsidered.

Correspondence

The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with
the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.

Indicate what change(s) you will implement in your practice, if any, based on this CME course.

Your quiz results:

The filled radio buttons indicate your responses. The preferred responses are highlighted

For CME Course:
A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes

Indicate what changes(s) you will implement in your practice, if any, based on this
CME course.

Instructions

Thank you for submitting a comment on this article. It will be reviewed by JAMA Internal Medicine editors. You will be notified when your comment has been published. Comments should not exceed 500 words of text and 10 references.

Do not submit personal medical questions or information that could identify a specific patient, questions about a particular case, or general inquiries to an author. Only content that has not been published, posted, or submitted elsewhere should be submitted. By submitting this Comment, you and any coauthors transfer copyright to the journal if your Comment is posted.

* = Required Field

Comment Author(s)* (if multiple authors, separate
names by comma)

Example: John Doe

Affiliation & Institution*

Disclosure of Any Conflicts of Interest*
Indicate all relevant conflicts of interest of each author below, including all relevant financial interests, activities, and relationships within the past 3 years including, but not limited to, employment, affiliation, grants or funding, consultancies, honoraria or payment, speakers’ bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued. If all authors have none, check "No potential conflicts or relevant financial interests" in the box below. Please also indicate any funding received in support of this work. The information will be posted with your response.

This feature is provided as a courtesy. By using it you agree that that you are requesting the material solely for personal, non-commercial use, and that it is subject to the AMA's Terms of Use. The information provided in order to email this article will not be shared, sold, traded, exchanged, or rented. Please refer to The JAMA Network's Privacy Policy for additional information.

Athens and Shibboleth are access management services that provide single sign-on to protected resources. They replace the multiple user names and passwords necessary to access subscription-based content with a single user name and password that can be entered once per session. It operates independently of a user's location or IP address. If your institution uses Athens or Shibboleth authentication, please contact your site administrator to receive your user name and password.